NK-1 receptor expressing cells are expressed on a variety of cell types. Thus, ablation of these cells can be a means to treat a variety of condition of modulate many different physiologic processes. For example, while pain-mediating cells and neurons are the predominant cells expressing NK-1 receptors (e.g., spiral cord dorsal horn neurons, see e.g., Basbaum (1999) Reg. Anesth. Pain Med. 24:59-67 ; brain cells, see, e.g., Saria (1999) Eur. J. Pharmacol. 375:51-60; neostriatum cells through the axon collarterals of spiny projection neurons, see, e.g., Galarraga (1999) Synapse 33:26-35), a variety of other cells also express NK-1 receptors. Thus, although pain relief is a major result of the killing of NK-1 receptor expressing cells, many other conditions can also be treated. For example, spinal NK-1 receptors modulate autonomic reflexes, including the micturition reflex. In the peripheral nervous system, NK-1 receptors are widely expressed in the respiratory, genitourinary and gastrointestinal tracts. NK-1 receptors are also expressed by several types of inflammatory and immune cells. In the cardiovascular system, NK-1 receptors mediate endothelium-dependent vasodilation and plasma protein extravasation. At respiratory level, NK-1 receptors mediate neurogenic inflammation which is especially evident upon exposure of the airways to irritants. In the carotid body, NK-1 receptors mediate the ventilatory response to hypoxia. In the gastrointestinal system, NK-1 receptors mediate smooth muscle contraction, regulate water and ion secretion and mediate neuro-neuronal communication. In the genitourinary tract, NK-1 receptors are widely distributed in the renal pelvis, ureter, urinary bladder and urethra and mediate smooth muscle contraction and inflammation in response to noxious stimuli. NK-1 receptors antagonists, including toxins that can ablate NK-1 receptor expressing cells, may have several therapeutic applications at sites in both the central and peripheral nervous systems and tissues of the body. In the central nervous system, NK-1 receptor ablation toxins could be used to produce analgesia, as antiemetics and for treatment of certain forms of urinary incontinence due to detrusor hyperreflexia. In the peripheral nervous system, toxins of the invention could be used in several inflammatory diseases including arthritis, inflammatory bowel diseases and cystitis (Quartara (1998) Neuropeptides 32:1-49). Thus, there exists a need to develop a wide variety of NK-1 expressing cell toxins for use as treatments for a variety of different conditions and as modifiers of a variety of different physiologic mechanisms.
Toxins which kill NK-1 expressing cells can be used to treat pain. In particular deman are toxins which can treat chronic pain while at the same time not significantly affecting the ability to react to acutely painful, potentially dangerous, stimuli. Efforts to find more effective treatments of chronic pain which have few unwanted side effects or which do not dampen acutely painful potentially dangerous stimuli remains a continuing challenge. Current analgesic therapies often fall short of therapeutic goals and typically have unacceptable side effects. In many chronic pain syndromes, such as those subsequent to neuropathic injury, pain is not well controlled by any currently available method. Furthermore, most chronic pain treatment regimes affect the patient's ability to perceive acute pain, thus blunting or abrogating necessary protective basal nociceptive responses. Thus, the discovery of more efficacious and safe means to control chronic pain is unpredictable and therapeutically advantageous.
An endogenous peptide ligand of NK-1 receptors is the eleven amino acid long peptide Substance P (“SP'). SP plays a central role in pain signaling by possibly transducing second messenger signals from primary afferent nociceptive terminals to second-order neurons in the spinal cord (see, e.g., Lembeck (1981) Neuropeptides 1:175-180). SP transduces a pain signal by interacting primarily with NK-1 receptor-bearing cells in the brain and spinal chord (see, e.g., Abbadie (1996) Neuroscience 70:201-209). Thus, one strategy to control pain has involved making SP antagonists or SP-based toxins that can selectively kill NK-1 receptor-bearing cells (see, e.g., Iadarola (1997) Science 278:239-240; Fitzgerald, D., pp. 69 to 82, In Towards a new Pharmacotherapy of Pain, Ed. A. I. Basbaum et al., John Wiley & Sons Ltd. 1991). For example, Goettl, et al. inhibited a pain response in mice by intrathecal administration of an SP antagonist (Goettl (1998) Brain Res. 780:80-85). Fisher et al. demonstrated that a diptheria toxin-SP recombinant protein selectively killed cultured cells stably transfected with and expressing NK-1 receptors (Fisher (1996) Neurobiol. 93:7344-7345). One group injected rats intrathecally with a saporin toxin-SP disulfide-linked conjugate. This conjugate killed NK-1 receptor bearing cells in the superficial lamina I of the spinal cord and reduced chronic but not acute pain sensation (Mantyh (1997) Science 278:275-279; Wiley (1997) Neurosci. Letters 230:97-100). Benoliel et al. selectively killed NK-1 receptor-bearing cells to reduce chronic pain in a rat animal model by intrathecal administration of an SP/diptheria toxin recombinant protein. The recombinant protein killed NK-1 receptor-bearing cells and significantly reduced chronic pain as compared to acute pain (Benoliel (1999) Pain 79:243-253). Thus, because of the potential for treating the very refractive and unpredictable condition of chronic pain, new NK-1 receptor bearing cell toxins are needed.
In summary, there exists a need to develop a wide variety of NK-1 expressing cell toxins for use as treatments for a variety of different conditions and as modifiers of a variety of different physiologic mechanisms, particularly in the unpredictable field of chronic pain control. It is also extremely important to provide patients with end stage disease proper palliative care and new mediations for control of severe intractable pain are needed for this population.